Thursday, March 12, 2015

The Search for a Regenerative Treatment for Damaged Salivary Glands

Most people have a friend or family member who has had cancer. The fight against cancer has been difficult because it has a multitude of causes, some of which are unknown and others of which are not well understood. And even though cancer researchers do most of the work towards creating cancer therapies and treatments, other labs are focusing on finding cancer treatments as well. For instance, the Hoffman lab at the National Institute of Dental and Craniofacial Research seeks to regenerate the salivary glands of head and neck cancer patients. There are thousands of new cases of head and neck cancer each year, and one of the common treatments for these cancers is radiotherapy. This method is often successful in killing tumor cells, but it also kills salivary gland cells, which are particularly susceptible to being damaged by radiation. So even after a cancer patient is diagnosed and gets successfully treated, there are more health problems to deal with. In mild cases, this can cause a slight but chronic dry mouth and throat; some are lucky and have so little salivary damage that they can live normal lives. But many have a moderately to severely dry throat for the rest of their lives. This is caused by a lack of saliva. Unfortunately, a lack of saliva also reduces one’s resistance to infection and increases the risk of developing dental and oral health maladies.

Obviously, even if a cancer treatment is successful, it may leave a person with other health problems. Research done at the Hoffman lab focuses on regenerating the salivary glands after they have been damaged by radiation therapy. The plan is to do this via stem cell therapy, whereby transcription factors (TFs) within the cell are stimulated to cause proliferation. A TF causes the transcription, and subsequent translation, of a gene into a protein. By taking advantage of molecular machinery which is already present in cells, stem cell therapy will heal the salivary glands without hurting other organs (assuming that the treatment is administered correctly). But in order to manipulate the cellular mechanisms which induce proliferation, these mechanisms must first be understood. Lombaert et al. 2013 provides the data which led to the discovery that two crucial cell membrane receptors, fibroblast growth factor receptor 2b (FGFR2b) and c-KIT (KIT), induce proliferation via cellular signaling pathways in developing salivary glands. The goal in Lombaert et al. 2013 is to use mice to study how salivary cells proliferate during development because these results are applicable to humans.

The receptors KIT and FGFR2b are already known to be important cell-surface receptors involved in several signaling pathways. KIT is a receptor tyrosine kinase, meaning that it is activated by the binding of a ligand, which causes a conformational change of the receptor. This phosphorylates a factor in the cytoplasm of the cell, which then starts a phosphorylation cascade wherein a chain of second messengers phosphorylate other molecules in the pathway. The end result of this is that a TF is activated, and the protein produced helps the cell adapt to its environment. FGFR2b functions very similarly to KIT, but it functions upstream of KIT.

Even though these receptors signal via different pathways, they work together during development to cause cell proliferation and create the salivary glands. These receptors work in a very similar fashion in other organs with a branching pattern, such as the lungs. The ligand for KIT is stem cell factor (SCF), while the ligand for FGFR2b is FGF10. Upon binding of each of these ligands to their respective cellular membrane receptors, the signaling cascade starts. The major finding of this paper is that each of these membrane receptors, when stimulated via addition of their ligand, will cause proliferation. However, the activation of both receptors (via addition of FGF10 and SCF) increases proliferation by a larger amount. FGFR2b is upstream of KIT and, when FGFR2b is activated, it both increases proliferation and upregulates the proliferation driven by KIT. These findings are invaluable for developing a way to regenerate the salivary glands. In order to move towards making FGFR2b and KIT stimulation therapeutically viable, the set of TFs activated which directly causes proliferation will need to be determined. A few of the top candidates include Sox10, Myc, and Etv4, but there are others whose importance in the pathway has not yet been realized.

In addition, there are a few other considerations to be made in developing a regenerative therapy. For instance, radiation blocks salivary function in part by destroying the nerves. As was found in Knox et al. 2013, adult salivary glands which have lost their parasympathetic innervation, but which retain their stem cells, will not regrow. But the restoration of parasympathetic innervation by a substance such as neurturin can lead to regeneration. Thus, the problem of regenerating glands is multifaceted, involving more than cell signaling pathways.

Finally, it is crucial to remember that stimulating cells to proliferate too much can lead to cancer, the disease for which this research is aiming to provide relief. Because of the exactness and care needed in administering stem cell therapy, the translation of this research into a treatment is likely not going to occur in the near future. However, because KIT and FGFR2b are found in several organs, especially in branching organs such as the lungs and salivary glands, the findings of this project could be used to create therapies for other damaged organs which need regeneration. While cancer biologists continue to develop more effective ways to treat and prevent cancer, organ therapy is still a promising option for those who must undergo the effective but harsh treatments available today. Even if a cure is found for cancer, this regenerative therapy still has importance for those with other salivary gland problems, and likely has applications for other organs.